ABSTRACT The objective of this STTR proposal is to reformulate a promising PEG-aptamer rapid onset anticoagulant (ROA) by applying a novel ?PEG-like? POEGMA polymer brush technology capable of eliminating anti-PEG antigenicity. The importance of this proposal is highlighted by the early termination of a recent Phase III clinical trial of the original PEG-aptamer conjugate in which severe allergic reactions occurred in individuals with high levels of pre-existing anti-PEG antibodies. As evidenced by this halted clinical trial, the effect of circulating anti-PEG antibodies is a growing concern due to the prevalence of anti-PEG found in individuals who are naive to PEGylated therapeutics?it has been suggested that the free PEGs present in commonly used consumer products are a likely source of these interfering anti-PEG antibodies. Our ?PEG-like? POEGMA polymer brush technology has been shown to confer the same PD/PK advantages of traditional PEG conjugates, while simultaneously eliminating anti-PEG antigenicity. We have shown that POEGMA, which breaks up the long sequences of repeating ethylene glycol units found in PEG and presents much shorter oligo(ethylene glycol) sequences, does not interact with anti-PEG antibodies. We expect that the application of POEGMA technology to the aptamer based ROA described here will allow for an effective therapeutic that does not suffer from a harmful interaction with pre-existing anti-PEG antibodies. Reformulating this aptamer ROA represents a useful application of the POEGMA technology, as there is an unmet clinical need for anticoagulants that can be rapidly reversed. Currently, approximately 12 million Americans per year require intravenous infusion of a highly potent, rapid onset anticoagulant to perform clinical procedures that are highly prothrombotic, including percutaneous coronary intervention (PCI, ?angioplasty?), coronary artery bypass graft (CABG) surgery and other surgeries, as well as dialysis. Significant disadvantages of current FDA-approved ROAs?unfractionated heparin (UFH), lepirudin, bivalirudin and argatroban?have prompted efforts to identify ROAs that eliminate the toxicity and drug induced bleeding associated with these ROAs. The PEG-aptamer sequence described here, together with the complementary antidote sequence capable of titrating and rapidly reversing anticoagulant activity, has been evaluated in >2,000 patients in Phase 1, Phase 2 and Phase 3 clinical trials, with phase 2 studies suggesting that this aptamer-antidote pair can reduce ischemic events and limit bleeding in PCI patients compared to heparin. Based on these promising results, we propose to eliminate the potential for the negative anti-PEG interactions that have stopped the development of this once promising PEG-aptamer therapeutic by developing a POEGMA-aptamer conjugate.